Usefulness of selective serotonin 5-HT6 receptor antagonists for treatment of CNS diseases, in particular, schizophrenia, AD and other neurodegenerative diseases and cognitive disorders was proved conclusively in clinical practice and is regarded to be very perspective in medicine of future [Holenz J., Pauwels P. J., Diaz J. L., Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT6 receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11:283-299]. At mammals these receptors are localized exclusively in CNS, and mainly in parts of brain responsible for training and memory [Ge'rard C., Martres M.-P., Lefe'vre K., Miguel M.-C., Verge' D., Lanfumey L., Doucet E., Hamon M., El Mestikawy S. Immuno-localisation of serotonin 5-HT6 receptor-like material in the rat central nervous system. Brain Research. 1997; 746:207-219]. Besides, it was shown, that 5-HT6 receptors are modulators of the whole number of neuromediator systems, including cholinergic, noradrenergic, glutamatergic and dopaminergic [Dawson L. A., Nguyen H. Q., Li P. The 5-HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus. Neuropsychopharmacology. 2001; 25:662-668]. Taking into account the fundamental role of these systems in normal cognitive processes and also their dysfunction at neurodegeneration, exclusive role of 5-HT6 receptors in forming normal and “pathological” memory becomes obvious. In a large number of nowadays publications it was shown that blocking of 5-HT6 receptors leads to considerable enhancement of memory consolidation in various animal models of training-memorizing-reproduction [Foley A. G., Murphy K. J., Hirst W. D., Gallagher H. C., Hagan J. J., Upton N., Walsh F. S., Regan C. M. The 5-HT(6) receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology. 2004; 29:93-100. Riemer C., Borroni E., Levet-Trafit B., Martin J. R., Poli S., Porter R. H., Bos M. Influence of the 5-HT6 receptor on acetylcholine release in the cortex: pharmacological characterization of 4-(2-bromo-6-pyrrolidin-1-ylpyridine-4-sulfonyl)phenylamine, a potent and selective 5-HT6 receptor antagonist. J. Med. Chem. 2003; 46:1273-1276. King M. V., Woolley M. L., Topham I. A., Sleight A. J., Marsden C. A., Fone K. C. 5-HT6 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing consolidation an effect sensitive to NMDA receptor antagonism. Neuropharmacology 2004; 47:195-204]. It was also demonstrated that considerable enhancement of cognitive functions in aged rats in Morrison's water maze experiment took place under the action of 5-HT6 receptor antagonists [Foley A. G., Murphy K. J., Hirst W. D., Gallagher H. C., Hagan J. J., Upton N., Walsh F. S., Regan C. M. The 5-HT(6) receptor antagonist SB-271046 reverses scopolamine-disrupted consolidation of a passive avoidance task and ameliorates spatial task deficits in aged rats. Neuropsychopharmacology. 2004; 29:93-100]. Recently more thorough understanding of 5-HT6 receptor function in cognitive processes and more accurate conceptions concerning possible pharmacophoric properties of their antagonists were achieved. [Holenz J., Pauwels P. J., Diaz J. L., Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT6 receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11:283-299]. This resulted in preparation of highly affine selective ligands (“molecular tools”), and afterwards clinical candidates. At present a number of 5-HT6 receptor antagonists are at various phases of clinical trial as potential ingredients for treatment of AD, Huntington's disease, schizophrenia (antipsychotic) and other neurodegenerative and cognitive diseases (Table 1) [http://integrity.prous.com].
TABLE 1Antagonists of 5-HT6 receptors as drug candidatesClinicalphase ofMedicamenttestingDeveloperTherapeutic groupDimebon ™Phase IIIMedivation (USA)Alzheimer's diseasetreatmentSGS-518Phase IILilly, SaegisCognitive diseasestreatmentSB-742457Phase IIGlaxoSmithKlineAlzheimer's diseasetreatment; AntipsychoticDimebon*Phase I/IIaMedivation (USA)Huntington's diseasetreatmentDimebon*Phase II(Russia)SchizophreniaPRX-07034Phase IEpix Pharm.Obesity treatment;Antipsychotic;Cognitive diseasestreatmentSB-737050APhase IIGlaxoSmithKlineAntipsychoticBVT-74316Phase IBiovitrumObesity treatmentSAM-315Phase IWyeth Pharm.Alzheimer's diseasetreatmentSYN-114Phase IRoche, SynosisCognitive diseasesTher.treatmentBGC-20-761PreclinicalBTG (London)Antipsychotic;Cognitive diseasestreatmentFMPOPreclinicalLillyAntipsychoticDimebon ™Preclinical(Russia)Insult treatment
Another attractive property of 5-HT6 receptor antagonists is their ability to suppress appetite that can lead to preparation of essentially novel remedies for overweight lowering and obesity treatment on their basis. [Vicker S. P., Dourish C. T. Serotonin receptor ligands and the treatment of obesity. Curr. Opin. Investig. Drugs. 2004; 5:377-388]. This effect was confirmed in many investigations [Holenz J., Pauwels P. J., Diaz J. L., Merce R., Codony X., Buschmann H. Medicinal chemistry strategies to 5-HT6 receptor ligands as potential cognitive enhancers and antiobesity agents. Drug Disc. Today. 2006; 11:283-299. Davies S. L. Drug discovery targets: 5-HT6 receptor. Drug Future. 2005; 30:479-495], the mechanism of it is based on the suppression of γ-aminobutyric acid signaling by 5-HT6 receptor antagonists and increasing of α-melanocyte-stimulating hormone emission, that, finally, results in lowering of food demand [Woolley M. L. 5-HT6 receptors. Curr. Drug Targets CNS Neurol. Disord. 2004; 3:59-79]. Now two antagonists of 5-HT6 receptors are at the first phase of clinical testing as drug candidates for obesity treatment (Table 1) [http://integrity.prous.com].
In this context searching for new selective and effective serotonin 5-HT6 receptor antagonists seems to be original and perspective approach to the development of novel drug substances for treatment of a great number of neurological and neurodegenerative diseases and cognitive disorders.
In scientific literature there are many publications dedicated to various biologically active arylsulfonyl substituted azaheterocycles, among them serotonin receptor ligands. For example, substituted 1-(2-aminoethyl)-4-(arylsulfonyl)pyrazoles of the general formula A1 were described as serotonin 5-HT2c receptor ligands [WO 2003057674 A1] and substituted 7-amino-3-(sulfonyl)pyrazolo[1,5-a]pyrimidines A2 as serotonin 5-HT6 receptor antagonists [EP 9411994 A1, 1999]
    A1: Ar=alkyl, aryl; R1 and R2=H, OH, alkyl, alkoxy; R3 and R4=H, alkyl, aryl.    A2: Ar=aryl, heterocyclyl; R1=H, alkyl, alkylthio; R2=H, alkyl, halogen; R3=H, alkyl, hydroxyalkyl; R4 and R5=H; NR4R5=piperazinyl.
With the aim of the development of novel highly effective medicament the authors of the invention carried out widespread investigation in the field of substituted 3-(arylsulfonyl)-pyrazolo[1,5-a]pyrimidines, as a result of which novel substituted 3-arylsulfonyl-pyrazolo[1,5-a]pyrimidines and novel drug substances which are selective 5-HT6 receptor antagonists have been found.